Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/24—Oxygen atoms attached in position 8
  • C07D215/26—Alcohols; Ethers thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D215/14—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

• the subject of the present invention is quinoline derivatives endowed in particular with inhibitory properties of the integrase of the human immunodeficiency virus.
• integrase inhibitor is ipso facto a candidate for blocking HIV infection, and possibly an effective therapeutic agent.
• integrase is the last to be the target of no therapeutic agent. In the context of polytherapy which currently seems to be the only way capable of effectively combating the rapid evolution of the virus, obtaining an integrase inhibitor is an essential objective.
• the object of the invention is therefore to provide new quinoline derivatives capable in particular of inhibiting HIV integrase activity in vitro and in vivo. It also relates to a process for the synthesis of these derivatives which is easy to use on an industrial scale.
• Another object of the invention is to take advantage of the anti-integrase properties of these derivatives for the preparation of medicaments.
• R b may also represent a hydrogen atom, and when Y represents a -COOH or -COOR group in R c , Z, if it represents an aryl group, contains at least 3 substituents or the quinoline nucleus is trisubstituted,
• - X represents an ethylenic double bond; or a group chosen from - (CH 2 ) n -, where n is an integer from 1 to 5; -CH (R d ) -CH (R e ) -, R d and R e> identical or different, representing a hydrogen or halogen atom, a hydroxy or epoxy group; - (CH 2 ) n , -0-C (0) - (CH 2 ) m -,
• aryl radical is meant a phenyl or naphthyl radical.
• Heterocycle designates 5 or 6 element cyles comprising one, two, three or four hetero atoms, chosen from N, S or 0.
• Heterogen designates a fluorine, chlorine, bromine atom or a tritralogenomethyl group, in particular trichloromethyl.
• Alkyl without further specification means a radical of 1 to 5 carbon atoms.
• a preferred family of derivatives according to the invention comprises at least one ethylenic double bond. They are in particular derivatives in which R a and / or X represent an ethylenically unsaturated group.
• X represents an ethylenic double bond
• X represents a group -CH (R d ) -CH (R e ) -, or - (CH 2 ) a - and R a has the meanings given in relation to the group above.
• X represents an ethylenic double bond and R a is a radical chosen from -OH, -COOH, or a pharmaceutically acceptable salt, or CN.
• R a is a radical chosen from -OH, -COOH, or a pharmaceutically acceptable salt, or CN.
• -R a represents at least one substituent chosen from a group -OH, -COOH, or a pharmaceutically acceptable salt, or CN, preferably two substituents of which one is a group -OH and the other has one of the meanings above,
• -R c represents two or three substituents -OH.
• the quinoline derivatives do not contain an ethylenic double bond.
• a preferred group of this family consists of derivatives in which R a represents a group - (CH 2 ) a -Y and X is a group -CH (R d ) -CH (R e ) -, or - (CH 2 ) a -.
• X comprises a hetero atom.
• n ' is an integer from 0 to_8
• m is an integer from 0 to 8
• t is zero or an integer equal to 1 or 2
• Q represents an atom hydrogen, an alkyl or aryl radical.
• Particularly advantageous products of the invention include 2- [2- [(3, 4-dihydroxyphenyl) ethenyl]] quinoline, 8-hydroxy-2- [2- [(3, 4-dihydroxyphenyl) ethenyl]] quinoline , 8-hydroxy- 2- [2- [(3, 4-dihydroxyphenyl) ethenyl]] 7-quinoline carboxylic acid, the sodium salt of 8-hydroxy-2- [2- [( 3,4-dihydroxyphenyl) ethenyl]] 7-quinolinecarboxylic, 7-cyano-8-hydroxy-2- [2- [(3, 4-dihydroxyphenyl) enhenyl]]] quinoline, 8-hydroxy-2 acid - [2- [(3, 4, ⁇ -trihydroxyphenyl) ethenyl]] 7-quinoline carboxylic, and 2- [2- [(3, 4-dihydroxyphenyl) ethenyl]] 5, 7-quinoline dicarboxylic acid.
• the invention also relates to a process for the synthesis of the derivatives defined above.
• This process is characterized in that it comprises
• a and B represent reactive groups capable of generating group X, as defined above, R a , R b , R c and Z having the meanings given in connection with formula I, but comprising blocking groups, and
• a Perkin type condensation between a quinaldin of formula V and an aromatic or heteroaromatic derivative of formula VI bearing the ⁇ rcuoes of bl ⁇ ca ⁇ e a ⁇ cro ⁇ riés:
• the process is carried out at reflux in a pyridine-water mixture for approximately 2 hours to 3 days.
• a quinaldin of formula V is advantageously reacted in which R a represents at at least one substituent chosen from the group -OH, or -COOH, or an oxime, and preferably two substituents, one of which is a group -OH, and the other has one of the meanings above, with a acetoxybenzaldehyde of formula VII:
• R c represents at least two -OH groups blocked by protective groups.
• the condensation step leads to the formation of quinoline derivatives comprising a double bond represented by X in formula I, and can be treated if desired, according to conventional techniques, to introduce the desired substituents R d and R e .
• the blocking groups are removed by hydrolysis.
• a ⁇ uinalcine derivative of formula VIII is used
• reaction being advantageously carried out in the presence of NaBH 3 CN in an acetic acid medium
• the derivatives of formula VIII in which W represents -NH 2 can be obtained by a process comprising: - the condensation of an aromatic amine _1 with an aldehyde 2_, by treatment in an acid medium, for example (HCl 6N ) and heating according to a reaction of
• a quinoline 3 is reacted with sodium hypochlorite, which makes it possible to obtain a 2-hydroxyquinoline derivative 6_, the treatment of which with phosphorus oxychloride provides a 2- chlcroquinoline 1_.
• the study of the biological properties of the derivatives of the invention has demonstrated an inhibitory activity with respect to integrase. of HIV, and of the enzyme EcoRI in vitro. In vivo experiments have also shown their inhibitory effect on HIV replication and the lack of effect on the late phases of HIV replication. These results are therefore of major interest for the treatment of an infection by this virus, all the more since the toxicity studies have demonstrated the high innocuity of these derivatives.
• the invention therefore relates to pharmaceutical compositions characterized in that they comprise an effective amount of at least one derivative as defined above, in combination with pharmaceutically acceptable vehicles.
• compositions are advantageously used in combination with other anti-HIV drugs, in particular drugs endowed with an inhibitory effect with respect to reverse transcriptase and / or prctease.
• the dosages and modes of administration will be adapted according to the mono-, bi- or triple therapy used.
• the invention also relates to the use of the derivatives defined above as biological reagents which can be used in particular for studies of mechanisms relating to viral infection.
• a mixture of quinaldine (0.90 g, 6.3 mmol) and 3,4-diacetoxybenzaldehyde (1.15 g, 7.0 mmol) in 10 ml of acetic anhydride is brought to reflux for 12 h.
• Step 2 Preparation of 2- [(3,4-dihydroxyphenyl) ethenyl] quinoline.
• step 2 To a solution of the above ester (step 1) (2.00 g, 5.76 mmol) in pyridine (20 ml) is added 8 ml of water. After 3 hours of reflux, the mixture is brought to 20 ° C., and 20 ml of dichloromethane are added. The phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, and concentrated under reduced pressure to give a yellow solid which is recrystallized from isopropanol. (1.51 g, 96%)
• a mixture of 8-hydroxyquinaldin (2.23 g, 14 mmol) and 3,4-diacetoxybenzaldehyde (2.6 g, 12 mmol) in 30 ml of acetic anhydride is brought to reflux for 12 h. After cooling to 20 ° C., the reaction mixture is concentrated under reduced pressure, taken up in ether and filtered.
• 8-hydroxy-7-quinaldine carbaldehyde (lg, 53 mmol) in acetic acid (20 ml) are successively added 0.73 g (10 mmol) of hydroxylated hydrochloride then 0.87 g (0.01 mmol) sodium acetate.
• 8-hydroxy-7quinaldine carbaldehyde is synthesized by operating according to Przystal et al, J. Heterocycl. Chem, 1967, 4, 131-2.
• 2 nd step preparation of 7-cyano-8-acetoxy-2- [(3, 4-diacetoxyphenyl) ethenyl] quinoline.
• a mixture of the 8-hydroxy-7-quinaldine carbaldehyde oxime (0.60 g, 2.9 mmol) and 3,4-diacetoxybenzaldehyde (0.78 g, 3.4 mmol) in 10 ml of anhydride acetic is brought to reflux for 12 h. After cooling to 20 ° C the reaction mixture is concentrated under reduced pressure.
• step 2 preparation of 7-cyano-8-hydroxy-2- [(3, 4-dihydroxyphenyl) ethenyl] quinoline.
• step 2 To a solution of the preceding triester (step 2) (0.60 g, 1.4 mmol) in pyridine (10 ml) is added 5 ml of water. After 3 hours of reflux, the mixture is brought to 20 ° C., and diluted with 20 ml of water. The phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, and concentrated under reduced pressure to give a yellow solid which is recrystallized from isopropanol (0.3 g, 71%). F 239-244 ° C
• a mixture of 8-hydroxyquinaldin carboxylic acid (0.23 g, 1.13 mmol) and 3,4,5-triacetoxybenzaldehyde (0.32 g, 1.16 mmol) in 7 ml of acetic anhydride is brought at reflux for 48 h. After cooling to 20 ° C. the reaction mixture is concentrated under pressure. The residue obtained is dissolved in pyridine (7 ml), 3 ml of water are added.
• HIV-1 integrase activity is measured by the following three tests:
• the strand transfer test is carried out with a double-stranded oligonucleotide of 21 pairs of bases mimicking the end of the viral DNA from which the 3 'terminal dinucleotide has been deleted.
• the activity of the protein results in the covalent insertion of this oligonucleotide into a homologous oligonucleotide.
• the disintegration test is carried out with a substrate mimicking the structure of the integrated viral DNA.
• the amount of DNA excised by the integrase is measured. This last test only quantifies the catalytic activity of the protein, excluding its binding activity on DNA.
• Compounds 1 and 3, according to the present invention inhibit the three activities of HIV-1 integrase.
• the inhibition of disintegration suggests that they are inhibitors of the catalytic activity of the enzyme.
• the degrees of inhibition in the three tests for each of the compounds are comparable, which shows that the compounds 1 and 3 do not disturb the binding of the integrase to its substrate.
• Table I indicates the inhibitory activities of the compounds according to the invention. The inhibition is expressed in the concentration necessary to block 50% of the activity of the HIV-1 integrase.
• Compound 2 which is the sodium salt of free acid 1, has the same anti-integrase activity as this in in vitro activity tests.
• the compound 2 is soluble in water at 10 mM while compound 1 is soluble in DMSO.
• the catalytic site of HIV-1 integrase is very close to that of the EcoRI restriction enzyme. Compounds that block both proteins are therefore catalytic integrase inhibitors.
• Compound 1 according to the present invention inhibits cleavage of a plasmid linearized by the enzyme EcoRI.
• the test is carried out as follows: The plasmid pSP65 is linearized and radiolabeled at its 5 ′ end by the polynucleotide kinase. The linearized plasmid is incubated for 4 hours in the presence of 0.1 units of the enzyme EcoRI. The activity of the enzyme is followed by the appearance of the cleavage products on 1.2% agarose gel.
• the specificity of the compounds according to the invention for integrase is estimated by an activity test on the reverse transcriptase enzyme of the HIV-1 virus. This test is carried out as follows: The viral particles of a culture supernatant of CEM cells (line established lymphocyte) are concentrated by centrifugation at 30,000RPM. These viral particles are lysed in a nonionic detergent and their reverse transcriptase activity is tested on a substrate formed from a hybrid oligo (dG) primer on a polyrC matrix. In the presence of radiolabelled dG nucleotide, the transcriptase activity results in the formation of labeled polynucleotide precipitable in trichloroacetic acid. It verifies that ddG dideoxynucleotide inhibits the formation of one acid-precipitable.
• dG dideoxynucleotide inhibits the formation of one acid-precipitable.
• the activity test consists in bringing cells of an established lymphocyte line, CEM cells, into contact with a supernatant of infected cells containing the infectious virions.
• the test is carried out as follows: CEM cells, cultured in suspension in RPMI medium supplemented with 10% fetal calf serum, are infected with a viral supernatant with a multiplicity of infection of 0.5. After 2 hours of infection, the cells are washed twice with RPMI medium so as to remove the residual viral particles. Finally, the cells are replaced in RPMI medium containing the compound according to the invention.
• the viral load is evaluated after 72 hours of culture. This is quantified in the following two ways: 1) The amount of viral protein p24 is determined by an ELISA test.
• the load of infectious virus is estimated by infection of the HeLa ⁇ -gal CD4 cells (see paragraph 4).
• the toxicity of the compounds is tested by a test for biotransformation of MTT into formazan by cellular mitochondrial dehydrogenases.
• compound 1 according to the present invention has a protective effect against infection of CEM cells by HIV-1.
• This protective effect results in an inhibition of the production of viral particles with a 50% efficiency of 4 ⁇ M according to the HeLa ⁇ -gal test and with a 50% efficiency of 28 ⁇ M according to the p24 test.
• Compound 1 is devoid of toxicity at 100 ⁇ M, maximum concentration tested, on CEM cells according to the MTT test.
• Compound 2 blocks the production of viral particles, measured by the p24 ELISA test, during infection of CEM cells. This compound is also devoid of toxicity according to the MTT test, up to 100 ⁇ M.
• the compounds according to the present invention were tested on the late stages of replication of the HIV-1.
• the test is as follows:
• the ACH2 cells which have integrated the HIV-1 viral DNA are used. These cells do not express viral proteins and therefore do not produce viruses unless activated by TNF. When cells are brought into the presence of TNF, they express HIV virus from the integrated provirus. The production of viral particles is detected 24 hours after activation. The viral load in the supernatant is quantified by ELISA test p24.

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• Quinoline Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Hydrogenated Pyridines (AREA)
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• 1997
  • 1997-04-08 FR FR9704289A patent/FR2761687B1/fr not_active Expired - Fee Related
• 1998
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